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Developmental origins and their associations with lineage plasticity and treatment response in B-cell progenitor acute lymphoblastic leukemia (B-ALL) are mostly unexplored. Here, we integrated single-cell transcriptome sequencing (scRNA-seq) of 89 B-ALL samples with a single-cell atlas of normal human B cell development incorporating functional and molecular assays. We observed subtype- and sample-dependent correlation with normal developmental stage, with intra-subtype and intra-patient...

Specific and biologically informed treatments for medulloblastoma, especially for the highly lethal TP53-mutant SHH subgroup, remain elusive, where radiotherapy is the primary treatment modality. Leveraging genome-wide CRISPR-Cas9 dropout screening in combination with lethal doses of radiotherapy, we identify loss of p53 as the main driver of radiation resistance in SHH medulloblastoma. A negative-selection CRISPR-Cas9 screen across multiple models of Trp53-deficient SHH medulloblastoma reveals...

Bipolar disorder is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 bipolar disorder risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci and prioritized 17 likely causal SNPs for bipolar disorder. We mapped these SNPs to genes and investigated their likely functional consequences by integrating variant annotations, brain...

CONCLUSION: Significantly more dysregulated proteins and biological pathways were found in males than in females with PsA. The identified proteins and pathways offer potential new targets for sex-based research in PsA.

This study explores the prevalence of yoga practice and associations with embodiment, internalized weight stigma, body satisfaction, unhealthy weight control behaviors, and binge eating in a diverse population-based sample. Data were collected as part of the Eating and Activity over Time (EAT) study. Participants include 994 adults (mean age: 27.6; range: 24-35), with high percentages from marginalized ethnic/racial and low-income backgrounds. Cross-sectional and five-year longitudinal analyses...

Determining the factors that impact the risk for infection with SARS-CoV-2 is a priority as the virus continues to infect people worldwide. The objective was to determine the effectiveness of vaccines and other factors associated with infection among Canadian healthcare workers (HCWs) followed from 15 June 2020 to 1 December 2023. We also investigate the association between antibodies to SARS-CoV-2 and subsequent infections with SARS-CoV-2. Of the 2474 eligible participants, 2133 (86%) were...

Current anomaly detection methods excel with benchmark industrial data but struggle with natural images and medical data due to varying definitions of 'normal' and 'abnormal.' This makes accurate identification of deviations in these fields particularly challenging. Especially for 3D brain MRI data, all the state-of-the-art models are reconstruction-based with 3D convolutional neural networks which are memory-intensive, time-consuming and producing noisy outputs that require further...

A critical assessment of computational hit-finding experiments (CACHE) challenge was conducted to predict ligands for the SARS-CoV-2 Nsp13 helicase RNA binding site, a highly conserved COVID-19 target. Twenty-three participating teams comprised of computational chemists and data scientists used protein structure and data from fragment-screening paired with advanced computational and machine learning methods to each predict up to 100 inhibitory ligands. Across all teams, 1957 compounds were...

Gene regulatory changes acting cis and trans to a gene can be inferred with allele-specific expression (ASE) transcriptomes from interspecies and inter-population hybrids and their parents. Problems of mapping bias and excessive information loss, however, can arise unintentionally from cumbersome analysis pipelines. We introduce CompMap, a self-contained method in Python that generates allele-specific expression counts from genotype-specific alignments. CompMap sorts and counts reads, not just...

Axial optical tweezers provide a natural geometry for performing biomechanical assays, such as rupture force measurements of protein binding. Axial traps, however, are typically weaker than their lateral counterparts and require high laser power to maintain a well-calibrated, linear restoring force. Here, we show how to extend the spatial range over which well-calibrated forces can be applied by considering aberration effects and extend the range of applied forces by accounting for the nonlinear...

CONCLUSIONS: We demonstrate that movement disorders in adults with 22q11.2DS exhibit greater clinical complexity than previously reported, which could reflect innate vulnerability and pathologic mechanisms beyond medication side effects. In those with a confirmed 22q11.2 microdeletion, periodic neurologic evaluations, supported by electrophysiologic investigations, enable accurate diagnosis and implementation of personalized management strategies.

CONCLUSION AND RELEVANCE: In this study, the identification of symptom groups of mental illness robustly defined by precisely characterized brain mechanisms enabled the characterization of dimensions of psychopathology based on quantifiable neurobiological measures.

Phenotypic screens of living organisms often require real-time, high spatial resolution imaging. We report here on the design and application of a line-scan imaging platform that enables bright-field imaging of live nematodes using a 96-well plate configuration. The system optics are such that each individual well is projected across the full field of view of a 4 K line scanning camera. To minimize motional artifacts, the camera system is translated, while the sample is kept stationary. We...

CONCLUSIONS: This is the first published clinical trial of a novel unidirectional brachytherapy device. CivaSheet proved to be a feasible technique to deliver intraoperative radiation to patients with high-risk pelvic malignancies after surgical resection, and warrants further study and clinical consideration, particularly in settings where other IORT options are not available.

Proteogenomics is limited by the challenge of modeling the complexities of gene expression. We create moPepGen, a graph-based algorithm that comprehensively generates non-canonical peptides in linear time. moPepGen works with multiple technologies, in multiple species and on all types of genetic and transcriptomic data. In human cancer proteomes, it enumerates previously unobservable noncanonical peptides arising from germline and somatic genomic variants, noncoding open reading frames, RNA...

Myelin ensheathment is essential for rapid axonal conduction, metabolic support and neuronal plasticity. In Alzheimer's disease (AD), disruptions in myelin and axonal structures occur, although the underlying mechanisms remain unclear. We implemented proximity labeling subcellular proteomics of the myelin-axon interface in postmortem human brains from AD donors and 15-month-old male and female 5XFAD mice. We uncovered multiple dysregulated signaling pathways and ligand-receptor interactions,...

Background: Beach volleyball (BVb) is a highly demanding Olympic sport characterized by intense physical activity and unique environmental challenges, including varying weather conditions and sandy, unstable court surfaces. Despite its popularity, there is a notable lack of scientific research addressing the metabolic and immune responses of elite female athletes in this sport. This study aims to address this gap by investigating two world-class Olympic medalists, female BVb players, who...

CONCLUSIONS: Findings indicate that dual inflammation exacerbates the acute phase clinical outcome of COVID-SZs. Suggesting a combined anti-inflammatory drug or the use of potentially anti-inflammatory antipsychotics in the acute phase of treatment to mitigate central nervous system damage. Regular monitoring of inflammatory marker levels can help reduce the risk of fluctuating psychiatric symptoms in patients with schizophrenia caused by inflammatory storms.

CONCLUSIONS: This work provides a platform for extending genome engineering in iPSCs to multiplexed assays of variant effects across diverse disease-relevant cellular phenotypes, enhancing the understanding of variant pathogenicity and uncovering novel biological mechanisms that could inform therapeutic strategies.